Nano-to-nano Fe/ppm Pd catalysis of cross-coupling reactions in water

ABSTRACT

In one embodiment, the present application discloses a catalyst composition comprising: a) a reaction solvent or a reaction medium; b) organometallic nanoparticles comprising: i) a nanoparticle (NP) catalyst, prepared by a reduction of an iron salt in an organic solvent, wherein the catalyst comprises at least one other metal selected from the group consisting of Pd, Pt, Au, Ni, Co, Cu, Mn, Rh, Ir, Ru and Os or mixtures thereof; c) a ligand; and d) a surfactant; wherein the metal or mixtures thereof is present in less than or equal to 50,000 ppm relative to the iron salt.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.62/163,466 filed May 19, 2015 and U.S. Provisional Application No.62/201,849 filed Aug. 6, 2015, which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Precious metal catalysis in organic synthesis, in large measure, hasbeen and continues to be among the most heavily utilized inroads to C—C,C—H and C-heteroatom bond constructions. Chief among these liespalladium chemistry, and with the 2010 Nobel Prizes recognizingPd-catalyzed Suzuki, Heck and Negishi couplings, even greater use ofthese and related processes are to be expected.^([1]) On the other hand,platinoids, in general, are now regarded as “endangered”; that is, theamount of such metals to which there is economical access is finite, andsupplies continue to dwindle. Thus, in a sense, award-winningorganopalladium chemistry might be viewed as at odds withsustainability. In one aspect, the coupling reactions utilizes micellarcatalysis in water and require no organic solvents.

To circumvent this situation, alternative metals have been studied, inparticular nickel^([2]) and copper,^([3]) especially as applied to themost heavily used Pd-catalyzed cross-coupling: Suzuki-Miyaurareactions.^([2a,2e,4]) While these have led to varying degrees ofsuccess, in the final analysis, Pd remains, by far, the metal of choice.Ideally, technology that accomplishes the desired transformations woulddo so at the ppm level of palladium. Furthermore, utilization of tracelevels of this metal, perhaps as found as an “impurity” in otherinexpensive metal salts, would ultimately translate into both arecycling of natural sources of Pd while the cost for its use,therefore, approaches zero.

SUMMARY OF THE INVENTION

The present application discloses a technology that takes a readilyavailable, earth-abundant iron salt that contains only parts per million(ppm) levels of Pd, and easily processes it into a very active catalystcapable of mediating cross-coupling reactions, such as Suzuki-Miyauracross coupling reactions, that may be performed in water as the reactionmedium, or water as the only reaction medium.

The following embodiments, aspects and variations thereof are exemplaryand illustrative are not intended to be limiting in scope.

In one embodiment, there is provided a catalyst composition comprising:a) a reaction solvent or a reaction medium; b) organometallicnanoparticles comprising: i) a nanoparticle (NP) catalyst, prepared by areduction of an iron salt in an organic solvent, wherein the catalystcomprises at least one other metal selected from the group consisting ofPd, Pt, Au, Ni, Co, Cu, Mn, Rh, Ir, Ru and Os or mixtures thereof; c) aligand; and d) a surfactant; wherein the metal or mixtures thereof ispresent in less than or equal to 50,000 ppm relative to the iron salt;or relative to the substrate.

In one variation of the above catalyst composition, the metal ormixtures thereof is present in less than or equal to 40,000 ppm, 30,000ppm. 20,000 ppm, 10,000 ppm, 5,000 ppm, 3,000 ppm, 2,000 ppm or 1,000ppm. In another variation, the metal or mixtures thereof is present inless than or equal to 1,000 ppm. In another variation of thecomposition, the surfactant provides nanomicelles for housing asubstrate. In another variation, the polar solvent or polar reactionmedium is water. In yet another variation, the polar solvent or polarreaction medium is a glycol or glycol ether selected fromethyleneglycol, propylene glycol, 2-methoxyethanol, 2-ethoxyethanol,2-propoxyethanol, 2-isopropoxyethanol, 2-butoxyethanol,2-phenoxyethanol, 2-benzyloxyethanol, 2-(2-methoxyethoxy)ethanol,2-(2-ethoxyethoxy)ethanol, 2-(2-butoxyethoxy)ethanol, dimethoxyethane,diethoxyethane and dibutoxyethane. In one variation of the above, theorganometallic nanoparticles are present as a complex. In anothervariation, the reaction medium is a micellar medium or an aqueousmicellar medium. In another variation, the catalyst composition furthercomprises water.

In another embodiment, there is provided an aqueous micellar compositionfor enabling cross-coupling reactions containing organometallicnanoparticles (NPs) as catalyst, comprising: a) an element selected fromthe group consisting of Fe, C, H, O, Mg, and a halide, or the entirecombination thereof; and b) palladium, or at least one other metalselected from the group consisting of Pt, Au, Ni, Co, Cu and Mn, or amixture thereof; wherein the catalyst (NPs) is prepared from a reductionof an iron salt in a solvent and in the presence of a ligand using areducing agent.

In one variation, there is provided an aqueous micellar composition forenabling cross-coupling reactions containing organometallicnanoparticles (NPs) as catalyst, comprising: a) an element selected fromthe group consisting of Fe, C, H, O, Mg, and a halide; and b) palladium,or at least one other metal selected from the group consisting of Pt,Au, Ni, Co, Cu, Mn, Rh, Ir, Ru and Os or a mixture thereof; wherein thecatalyst (NPs) is prepared from a reduction of an iron salt in a solventand in the presence of a ligand using a reducing agent, after which thesolvent is removed and to which is then added an aqueous solutioncontaining nanomicelles, wherein the palladium is present in less thanor equal to 1,000 ppm of the iron metal complex, and wherein the ligandis present in an amount, on a mole-to-mole basis, comparable to thelevels of iron salt being used.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the application discloses a catalyst compositioncomprising an aqueous micellar medium together with organometallicnanoparticles as a complex, comprising: a) a surfactant, providingnanomicelles for housing a substrate; b) a nanoparticle (NP) catalyst,prepared by a reduction of an iron salt, wherein the catalyst comprisesat least one other metal selected from the group consisting of Pd, Pt,Au, Ni, Co, Cu, Mn, Rh, Ir, Ru and Os or a mixture thereof; c) a ligand;and d) water; wherein the metal or a mixture thereof is present in lessthan or equal to 1,000 ppm of the iron catalyst.

In one variation of the catalyst composition, the nanomicelles house,enclose, encase or surround one or more substrates for a catalyticreaction as described herein. In one variation, the 1,000 ppm is basedon a mole to mole basis. In one variation, the relative ppm isdetermined on a wt/wt basis. In another variation, the other metal isselected from Pd, Pt and Ni, or a mixture thereof.

In another embodiment, there is provided an aqueous micellar compositionfor enabling cross-coupling reactions containing organometallicnanoparticles (NPs) as catalyst, comprising: a) an element selected fromthe group consisting of Fe, C, H, O, Mg, and a halide; and b) palladium,or at least one other metal selected from the group consisting of Pt,Au, Ni, Co, Cu, Mn, Rh, Ir, Ru and Os, or a mixture thereof; wherein thecatalyst (NPs) is prepared from a reduction of an iron salt in a solventand in the presence of a ligand using a reducing agent, after which thesolvent is removed and to which is then added an aqueous solutioncontaining nanomicelles, wherein the palladium is present in less thanor equal to 1,000 ppm of the iron metal complex, and wherein the ligandis present in an amount, on a mole-to-mole basis, comparable to thelevels of iron salt being used, or the levels of the substrate beingused.

In one aspect of the above composition, the iron is selected from thegroup consisting of a Fe(II) or Fe(III) salt, or a Fe(II) salt precursoror Fe(III) salt precursor. In one variation of the composition, thecatalyst comprising at least one other metal selected from the groupconsisting of Pd, Pt, Au, Ni, Co, Cu, Mn, Rh, Ir, Ru and Os is naturallypresent in the iron salt in amounts less than or equal to 1 ppm, 10 ppm,50 ppm, 100 ppm, 200 ppm, 300 ppm, 400 ppm or 500 ppm relative to theiron complex. In another variation, the iron salt is highly purifiediron, such as with an assay as >99.99% trace metal basis, or having lessthan 0.01% other metals, and the catalyst is added to the composition tobe present in the iron salt in an amount that is less than or equal to 1ppm, 10 ppm, 50 ppm, 100 ppm, 200 ppm, 300 ppm, 400 ppm or 500 ppmrelative to or within the iron complex, or the iron salt. In anothervariation, the catalyst is added prior to reduction and NP formation.

In one variation of the catalyst composition and the method disclosed inthe present application, the reaction solvent is water. In anothervariation, the reaction solvent is a mixture of water and an organicsolvent or co-solvent. In one variation, the composition comprises waterin an amount of at least 1% wt/wt of the mixtures. In anotherembodiment, the water in the mixture is present in an amount of at least5%, at least 10%, at least 50%, at least 75%, at least 90% or at least99% wt/wt or more of the mixture. In another variation, the organicco-solvent in the reaction solvent is present in at least 5%, 7%, 10%,15%, 20%, 30%, 40%, 50%, 70%, 80% or 90% with the remaining being wateror a polar solvent. In yet another variation, the organic co-solvent ispresent at a wt of organic co-solvent to the wt of water (wt/wt) of1/10, 2/10, 3/10, 5/10, 7/10, 9/10, 10/10, 12/10, 15/10, 17/10, 20/10,25/10, 30/10, 35/10, 50/10, 60/10, 70/10, 80/10, 90/10, 100/10, 150/10,200/10, 250/10, 300/10, 400/10, 500/10, 600/10, 700/10, 800/10, 900/10,1,000/10, 5,000/10 and 10,000/10. In one variation, the reaction may beperformed in one of the above reaction solvent composition by wt/wt(e.g., 1/10), as a first solvent composition, and when the reaction iscompleted, the reaction solvent composition may be changed to anothercomposition or second wt/wt composition (e.g., 150/10), to facilitate atleast one of the processing of the reaction mixture; transferring ofreaction mixture, isolating components of the reaction mixture includingthe product, minimizing the formation of emulsions or oiling out of thereactants and/or products, and providing an increase in the reactionyields; or a combination thereof. Depending on the reaction orprocessing steps, the reaction mixture may be changed to a third orother, subsequent solvent composition. In another aspect, water is theonly reaction medium in the mixture. In another aspect, non-exclusiveexamples of the organic solvent or co-solvent may include C₁-C₆ alcoholssuch as methanol, ethanol, propanol, isopropanol, butanol(s), n-butanol,2-butanol, etc . . . , hydrocarbons such as cyclohexane, heptane(s),hexanes, pentanes, isooctane, and toluene or xylenes, or acetone, amylacetate, isopropyl acetate, ethyl acetate, methyl acetate, methylformate, diethyl ether, cyclopropyl methyl ether, THF, 2-methyl-THF,acetonitrile, formic acid, acetic acid, ethyleneglycol or PEGs/MPEGs ofany length of ethylenoxy units, trifluoromethylbenzene, triethylamine,dioxane, sulfolane, MIBK, MEK, MTBE, DMSO, DMF, DMA, NMP or mixturesthereof.

In one variation of the above, there is provided a composition, such asthe catalyst composition, prepared by the above described process. Inone variation of the above composition, the halide is Cl or Br. Inanother variation, the other metal may be present in any of theiroxidation states, including 1, 2, 3, 4 or 5. In one aspect of the abovecomposition, the reducing agent is a Grignard reagent. In one variationof the composition, the reduction of the iron salt is performed in anether solvent. In one variation, the ether solvent is selected from thegroup consisting of methyl ether, ethyl ether, THF, Me-THF, dioxane,mono-glyme and di-glyme. In one variation of the composition, thesolvent is selected from the group consisting of THF, Methyl-THF,toluene, i-PrOAc, MTBE and mixtures thereof. In another variation, thereduction is performed at a temperature between −25° C. and 25° C. Inone aspect, the ligand is present in about a 1:1; 1:1.1; 1:1.2; 1:1.3;1:1.4 or 1:1.5; or 1.5:1; 1.4:1; 1.3:1; 1.2:1; 1.1:1 on a mole-to-molebasis to the levels of iron salt being used. In one embodiment, there isprovided a composition prepared by the above method.

In another aspect of the above composition, the iron is selected fromthe group consisting of a Fe(II) or Fe(III) salt as precursor to thecatalyst. In another aspect of the composition, the palladium isnaturally present in the iron salt in amounts less than or equal to 500ppm relative to the iron complex.

In one variation of the composition, the Pt, Au, Ni, Co, Cu, Mn, Rh, Ir,Ru and Os or a mixture thereof is naturally present in less than orequal to 500 ppm (0.05 mole %) within the iron salt. In anothervariation of the composition, the Pt, Au, Ni, Co, Cu, Mn, Rh, Ir, Ru andOs or a mixture thereof is added to the composition in less than orequal to 1,000 or 500 ppm within the iron salt.

In another aspect, the amount of Pd present is controlled by externaladdition of a Pd salt to an iron salt prior to reduction and NPformation. In one variation of the composition, the iron is a purifiediron salt, such as a highly purified iron salt, such as FeCl₃ or ahighly purified FeCl₃. In another variation, the iron salt, such asFeCl₃, has an assay of >99.99% trace metal basis, or less than 0.01%other metals. In another variation, the iron salt is purified withsubstantially no palladium. In one variation of the composition, theamount of Pd present by external addition of a Pd salt may be about1-50,000 ppm, 1-1,000 ppm, 1-500 ppm, 1-300 ppm or 1-200 ppm; 100 ppm,200 ppm, 300 ppm, 500 ppm or 1000 ppm or more.

In another aspect of the composition, the reducing reagent is a Grignardreagent selected from the group consisting of MeMgCl, MeMgBr, MeMgI,EtMgCl, EtMgBr, EtMgI, i-PrMgCl, i-PrMgBr, i-PrMgI, PhMgCl, PhMgBr,PhMgI, n-hexyl-MgBr, n-hexyl-MgCl, n-hexyl-MgBr, n-hexyl-MgCI,n-hexyl-MgI, NaBH₄, liBH₄, BH₃-THF, BH₃—SMe₂, borane, DIBAL-H andLiAlH₄; and mixtures thereof. In one variation of the composition, theGrignard reagent is in an ethereal solvent. In another variation, thesolvent is THF.

In another aspect, the surfactant is selected from the group consistingof TPGS-500, TPGS-500-M, TPGS-750, TPGS-750-M, TPGS-1000 andTPGS-1000-M, Nok and PTS. In one variation of the composition, thesurfactant is selected from the group consisting of Poloxamer 188,Polysorbate 80, Polysorbate 20, Solutol HS 15, PEG-40 Hydrogenatedcastor oil (Cremophor RH40), PEG-35 Castor oil (Cremophor EL),PEG-8-glyceryl capylate/caprate (Labrasol), PEG-32-glyceryl laurate(Gelucire 44/14), PEG-32-glyceryl palmitostearate (Gelucire 50/13);Polysorbate 85, Polyglyceryl-6-dioleate (Caprol MPGO), Sorbitanmonooleate (Span 80), Capmul MCM, Maisine 35-1, Glyceryl monooleate,Glyceryl monolinoleate, PEG-6-glyceryl oleate (Labrafil M 1944 CS),PEG-6-glyceryl linoleate (Labrafil M 2125 CS), Propylene glycolmonocaprylate (e.g. Capmul PG-8 or Capryol 90), Propylene glycolmonolaurate (e.g., Capmul PG-12 or Lauroglycol 90), Polyglyceryl-3dioleate (Plurol Oleique CC497), Polyglyceryl-3 diisostearate (PlurolDiisostearique) and Lecithin, or mixtures thereof. In another variation,the surfactant is selected from the group consisting of Solutol HS 15,PEG-40 Hydrogenated castor oil (Cremophor RH40), PEG-35 Castor oil(Cremophor EL), Polysorbate 85, or mixtures thereof. In anothervariation, the surfactant is present as a 0.1 to 20 weight % in water, 1to 5 weight % in water, or 2 weight % in water. In another aspect, thecomposition further comprises an organic solvent.

In another aspect, the composition further comprises a ligand, such as amono- or bi-dentate phosphine or NHC ligand selected from the groupconsisting of PPh₃, (o-Tol)₃P, (p-Tol)₃P, dppf, dtbpf, BiDime, Tangphos,IMes, IPr, SPhos, t-BuSPhos, XPhos, t-BuXPhos, BrettPhos andt-BuBrettPhos, and HandaPhos or an analog thereof. In another aspect ofthe composition, the iron metal complex as nanoparticles isheterogeneous and can be isolated from the composition, stored andrecycled and re-use.

In another embodiment, there is provided a method for performing a crosscoupling reaction between a first coupling substrate of the formula Iwith a second coupling substrate of the formula II in a reactioncondition sufficient to form the coupled product of the formula III:

wherein: X is selected from the group consisting of Cl, Br and I; Y isselected from the group consisting of B(OH)₂, B(OR)₂, cyclic boronates,acyclic boronates, B(MIDA), Bpin and BF₃K, where R is selected frommethyl, ethyl, propyl, butyl, isopropyl, ethylene glycol, trimethyleneglycol and pinacol;

each of the groups

is independently selected from the group consisting of an alkene or asubstituted alkene, a cycloalkene or a substituted cycloalkene, analkyne or a substituted alkyne, an aryl or a substituted aryl, and aheteroaryl or a substituted heteroaryl; the method comprising: i)forming a micelle composition comprising aqueous nanoparticles in whichthe partners I and II are solubilized in water, and an organometalliccomplex comprising: a) iron nanoparticles, wherein another metal ispresent in less than 50,000 ppm, or less than 1,000 ppm; b) other metalnanoparticles admixed with iron nanoparticles; and ii) contacting thefirst coupling substrate with the second coupling substrate in waterunder a condition sufficient to form a product mixture comprising across coupling product of the formula III.

In another embodiment, there is provided a method for performing a crosscoupling reaction between a first coupling substrate of the formula Iwith a second coupling substrate of the formula II in a reactioncondition sufficient to form the coupled product of the formula III:

wherein: X is selected from the group consisting of Cl, Br and I, andpseudo halides; Y is selected from the group consisting of B(OH)₂,B(OR)₂, cyclic boronates, acyclic boronates, B(MIDA), Bpin and BF₃K,where R is selected from methyl, ethyl, propyl, butyl, isopropyl,ethylene glycol, trimethylene glycol and pinacol;

each of the groups

is independently selected from the group consisting of an alkene or asubstituted alkene, a cycloalkene or a substituted cycloalkene, analkyne or a substituted alkyne, an aryl or a substituted aryl, and aheteroaryl or a substituted heteroaryl; the method comprising: i)forming a micelle composition comprising aqueous nanoparticles in whichthe partners I and II are solubilized in water, and an organometalliccomplex comprising iron nanoparticles, wherein another metal is presentin less than 50,000 ppm relative to the limiting substrate of theformula I or formula II; and ii) contacting the first coupling substratewith the second coupling substrate in water under a condition sufficientto form a product mixture comprising a cross coupling product of theformula III. In one variation of the method, the metal or mixturesthereof is present in less than or equal to 40,000 ppm, 30,000 ppm,20,000 ppm, 10,000 ppm, 5,000 ppm, 3,000 ppm, 2,000 ppm or 1,000 ppm.

In one variation of the above method, the other metal (i.e., the“another metal” that is other than iron cited above) is palladium. Inanother variation, the other metal is present in less than 700 ppm, 500ppm or 300 ppm. In one variation of the method, the micelle compositionis a catalyst composition comprising an aqueous micellar medium togetherwith organometallic nanoparticles as a complex, comprising: a) asurfactant, providing nanomicelles for housing a substrate; b) ananoparticle (NP) catalyst, prepared by a reduction of an iron salt,wherein the catalyst comprises at least one other metal selected fromthe group consisting of Pd, Pt, Au, Ni, Co, Cu, Mn, Rh, Ir, Ru and Os ora mixture thereof; c) a ligand; and d) water; wherein the metal or amixture thereof is present in less than or equal to 50,000 ppm or 1,000ppm relative to the substrate. In another variation of the method, thecoupling reaction is performed between room temperature, or about 20° C.and 50° C.

In another aspect of the above method, the metal, other than Pd, isselected from the group consisting of Pt, Au, Ni, Co, Cu, Mn, Rh, Ir, Ruand Os or a mixture thereof. In another aspect, the method furthercomprises: iii) contacting the product mixture with an organic solventto form an organic phase and an aqueous phase; and iv) separating theorganic phase from the aqueous phase containing the micelle compositionas well as the iron/ppm Pd nanoparticles.

In another aspect, the method further comprising: v) re-cycling theaqueous phase containing the micelle composition and Fe/ppm Pdnanoparticles for use in a subsequent cross coupling reaction. Inanother aspect of the method, the source of iron is selected from FeCl₃,impure FeCl₃ and mixtures thereof, and the reducing agent is a Grignardreagent. Impure FeCl₃ include 96%, 97%, 98%, 99%, 99% or >99% purity. Inanother aspect of the method, the reaction condition is a Suzuki-Miyauracoupling condition or a Sonogashira coupling condition, or other commonPd-catalyzed cross-coupling reactions. In one variation of the above,the reaction is an amination reaction, Stille couplings, Negishicouplings, Hiyama couplings and cross-couplings involving oxygennucleophiles. In another aspect of the method, the reaction is performedat room temperature. In one variation of the above, the reaction isperformed at about 20 to 65° C., 20 to 45° C., or 15 to 35° C.

In yet another aspect of each of the above, the method further comprisesremoval of the solvent in vacuo, and further isolating the nanoparticlesfrom the reaction mixture for re-use or recycling. In another aspect,the method further comprises removal of the solvent in vacuo, andfurther isolating the nanoparticles from the reaction mixture for re-useor recycling. In one variation, the nanoparticles may be re-use orrecycled for 2, 3, 4, 5 or more reactions or processes.

In one variation of the above, the nanoparticles (NPs) are powders. Inanother variation of the composition, the Pd is present in any of itsoxidation states, such as Pd^(o), Pd(I), Pd(II) or Pd(IV). In onevariation, the metal is a trace impurity (e.g., in ppm) in the ironsalt. In another variation, the metal is added to the compositioncomprising the organometallic complex before the addition of thereducing agent.

In one embodiment, the application discloses composites or compositionscomprising nanoparticles (NPs) as powders derived from an iron (Fe)metal, such as an Fe(II) salt or an Fe(III) salt. In one aspect, the NPscontain primarily C, H, O, Mg, halogen and Fe in their matrix. Inanother aspect, these NPs may also contain ppm levels of other metals,especially transition metals (e.g., Pd, Pt, Au, Ni, Co, Cu, Mn, Rh, Ir,Ru and Os, and mixtures thereof), that may be either present in theFe(II) or Fe(III) salts or the transition metals may be added externallyprior to reduction (e.g., using Pd(OAc)₂, etc.). In one variation, thetransition metal is Pd, Pt or Ni, or a mixture thereof. In the resultingcomposite, these NPs may be used as heterogeneous catalysts, in anaqueous micellar medium. In another aspect, the NPs maybe used tomediate transition metal-catalyzed reactions. Such metal-catalyzedreactions may include reactions that are catalyzed by Pd (e.g.,Suzuki-Miyaura and Sonogashira couplings, etc.), as well as reductionsof selected functional groups (e.g., aryl/heteroaryl nitro groups).

In one variation of the above composition, the nanoparticleorganometallic complex consists mainly of iron. In another variation,the nanoparticle organometallic complex comprises of a mixture of metalswherein at least 90% wt/wt, 95% wt/wt, 97% wt/wt, 98% wt/wt, 99% wt/wt,99.5% wt/wt, 99.8% wt/wt or 99.9% wt/wt of the metal is iron. In onevariation of the complex, the other metal present in the mixture ispalladium.

In one aspect of the composition, the iron metal is selected from thegroup consisting of a Fe(II) or Fe(III) salt or salt precursor. In onevariation, the iron metal is FeCl₃.

In another aspect, the palladium is present in the iron metal complex inamounts less than or equal to 400 ppm relative to the iron metalcomplex. In one variation, the palladium is Pd⁰, prepared by reductionof Pd(OAc)₂ or other Pd salts. In another variation, the iron metalcomplex is doped by addition of the palladium, before or after reductionof the iron salt. In another variation of the above composition, thepalladium is present in less than about 800 ppm, less than 700 ppm, lessthan 600 ppm, less than 500 ppm, less than 400 ppm, less than 300 ppm,less than 200 ppm or less than 100 ppm.

In another aspect, the iron metal complex as nanoparticles isheterogeneous and can be isolated, stored and recycled. In one variationof the above composition, the nanoparticle complex may be stored at roomtemperature for at least 1 month, 2 month, 3 months, 4 months, 5 monthsor more than 6 months without any noticeable degradation.

In one variation, the compound of the formula I and the compound of theformula II may also include any sp2-sp2 combination, includingcyclopropyl arrays. In one aspect of the above, the metal is Pd, Pt orNi, or mixtures thereof. In another variation of the above, the ironmetal complex containing palladium metal as nanoparticles is present atless than about 10 mol percent (mol %), 8 mol percent, 6 mol percent, 5mol percent, 3 mol percent, 2 mol percent or less than about 1 molepercent relative to the first coupling substrate of the formula I or thesecond coupling substrate of the formula II.

In another variation of the above, the substituent is 1, 2 or 3substituents selected from the group consisting of —OCH₃, —CF₃, —NR¹R²,—CH(OC₁₋₆ alkyl)₂, —C(O)NR¹R², —CHO, —CO₂C₁₋₁₂ alkyl, —CO₂C₆₋₁₂ aryl,—CO₂C₃₋₁₀ heteroaryl, —C(O)C₆₋₁₂ aryl, —C(O)C₃₋₁₀heteroaryl, whereineach R¹ and R² is independently selected from H and C₁₋₆ alkyl.

In another aspect of the above, the method further comprises: iii)contacting the product mixture with an organic solvent to form anorganic phase and an aqueous phase; iv) separating the organic phasefrom the aqueous phase containing the micelle composition as well as theiron/ppm Pd nanoparticles.

In another aspect of the above, the method further comprises v)re-cycling the aqueous phase containing the micelle composition andFe/ppm Pd nanoparticles for use in a subsequent cross coupling or otherreactions. In another aspect of the above method, the source of iron isselected from FeCl₃, impure FeCl₃ and mixtures thereof. In anotheraspect, the reducing agent is a Grignard reagent. In one variation ofthe above, there is provided a catalyst composition prepared by theabove described process.

This technological advance is based on the confluence of severalreaction variables: The choice and source of the iron salt, the methodfor its conversion to nanoparticles, and the use of micellar catalysisconditions. In one aspect, the treatment of FeCl₃ or impure FeCl₃ withan equivalent of MeMgCl in a minimal amount of a solvent, such as anether, such as THF, at room temperature affords nanoparticles that,after solvent removal in vacuo, can be used directly in a cross couplingreaction. Alternatively, these particles may be isolated, such as byfiltration, and stored at room temperature for months without anynoticeable degradation.

EXPERIMENTAL

The following procedures may be employed for the preparation of thecompounds of the present invention. The starting materials and reagentsused in preparing these compounds are either available from commercialsuppliers such as the Aldrich Chemical Company (Milwaukee, Wis.), Bachem(Torrance, Calif.), Sigma (St. Louis, Mo.), or are prepared by methodswell known to a person of ordinary skill in the art, followingprocedures described in such references as Fieser and Fieser's Reagentsfor Organic Synthesis, vols. 1-17, John Wiley and Sons, New York, N.Y.,1991; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supps.,Elsevier Science Publishers, 1989; Organic Reactions, vols. 1-40, JohnWiley and Sons, New York, N.Y., 1991; March J.: Advanced OrganicChemistry, 4th ed., John Wiley and Sons, New York, N.Y.; and Larock:Comprehensive Organic Transformations, VCH Publishers, New York, 1989.

In some cases, protective groups may be introduced and finally removed.Suitable protective groups for amino, hydroxy and carboxy groups aredescribed in Greene et al., Protective Groups in Organic Synthesis,Second Edition, John Wiley and Sons, New York, 1991. Standard organicchemical reactions can be achieved by using a number of differentreagents, for examples, as described in Larock: Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

Analysis of a commercially available source^([11]) of FeCl₃ by atomicabsorption-ICP led to the finding that approximately 300-350 ppm Pd arepresent. In some aspects, the sources of FeCl₃ that analyzed for less ofthis metal content^([11b]) led to incomplete reactions under otherwiseidentical conditions. Attempts to use ppm levels of Pd in the absence ofpre-formed iron-based nanoparticles led to virtually no reaction,suggesting that release of palladium into the aqueous medium is notresponsible for the observed catalysis. Doping of highly purified FeCl₃(99.9999%)^([11b,12]) with 350 ppm Pd(OAc)₂, upon reduction with MeMgCl,gave reagent of comparable activity. Doping the FeCl₃ with ppm levels ofother metals, such as NiCl₂, CoCl₃, Cu(OAc)₂ or CuBr₂ led to catalyststhat gave variable levels of product formation; in all cases the yieldswere considerably lower than those obtained in the presence of addedPd(OAc)₂ (Table 1).

TABLE 1 Attempts to dope FeCl₃ with alternative metals

entry doped metal R % yield  1. NiCl₂, Ni(acac)₂ H NR  2. NiCl₂,Ni(acac)₂ OMe NR  3. NiCl₂, Ni(acac)₂ Me NR  4. CoCl₃ H 15%  5. CoCl₃OMe 18  6. CoCl₃ Me 38  7. MnCl₂ H  5%  8. MnCl₂ OMe NR  9. MnCl₂ Me NR10. Cu(OAc)₂, CuBr₂ H NR

The nature of the iron salt plays a major role in the activity of theresulting nanoparticles formed, as does the manner in which the salt isreduced. Attempts to use either Fe(acac)₃ or iron pyrophosphate(Fe₄(P₂O₇)₃) as precursors led to a far less reactive catalyst than thatderived from FeCl₃. In some aspects, the nature of the reducing agent isalso important. While use of i-PrMgCl led to a reagent of comparableactivity, both PhMgCl and n-hexyl-MgBr, among other reductants (e.g.,NaBH₄) afforded nanoparticles that were inferior in a standardSuzuki-Miyaura coupling (Table 2).

TABLE 2 Impact of the reducing agent on the activity of ironnanoparticles

Reductant (6 mol %) % 1 NaBH₄ 28 iPrMgCl 92 HexMgBr 75 PMHS  5 PhMgCl 76MeMgCl 95 MeMgBr 93

In one aspect, only 3 mol percent of these Fe/ppm Pd nanoparticles isneeded, to which are added an aqueous solution containing 2 weightpercent of a commercially available designer surfactantTPGS-750-M,^([5]) followed by a base (K₃PO₄; 1.5-2.0 equiv; Scheme 1).The choice of ligand was also significant (Scheme 2), with bothSPhos^([6]) and XPhos^([7]) affording the best results (Scheme 2).Depending upon the reaction partners, vigorous stirring at temperaturesbetween ambient and 45° C. is sufficient to drive couplings tocompletion. In certain aspects, the reactions are typically complete inthe 12-24 hour time frame. In some aspects, the reactions are conductedat a global concentration of 0.5 M.

Scheme 2. Impact of ligand on the cross-coupling. Entry Ligand % Yield 1None none 2 PPh3 28 3 dppf 70 4 dtbpf 75 5 Bidime 18 6 Tangphos 69 7IMes 50 8 IPr 70 9 SPhos 98 10 tBuSPhos 92 11 XPhos 94 12 tBuXPhos 89 13BrtettPhos 44 14 tBuBrrettPhos 40

Many representative cases illustrated in Tables 3-5. A broad variety ofaromatic and heteroaromatic arrays, with either being the aryl halide orboron-containing source, can be tolerated, as can numerous functionalgroups dispersed throughout either coupling partner. Thus, functionalitysuch as CF₃, amines, acetals, amides, aldehydes, esters, ketones,phosphate esters, nitro groups, polyaromatics, sulfonamides andcarbamates are exemplified.

Several types of heteroaromatic units are also amenable, includingnitrogen-containing moieties, the products from which might presentcomplications as competing ligands for Pd. Both bromides and iodides areexcellent educts, while the nature of the boron species involved can beany of the commonly employed boronic acids, Bpin^([8]) or MIDAboronates,^([9]) or BF₃K salts.^([10])

TABLE 3 Couplings between aryl halides and aryl boron derivatives

TABLE 4 Suzuki-Miyaura couplings between aryl and heteroaryl partners

TABLE 5 Suzuki-Miyaura couplings between heteroaryl and heteroarylpartners

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Preparation of Fe/Ppm Pd Nanoparticles (NPs) for SM Cross-Couplings:

In a flame dried two-neck round-bottomed flask, anhydrous pure FeCl₃(500 mg, 3.09 mmol), SPhos (1015 mg, 2.47 mmol), and Pd(OAc)₂ (6.0 mg,0.027 mmol) were placed under an atmosphere of dry argon. The flask wasclosed with a septum, and dry THF (8 mL) was added. The reaction mixturewas stirred for 20 min at RT. While maintaining a dry atmosphere at RT,MeMgBr (12.4 ml, 6.18 mmol; 0.5 M solution) in THF was very slowly (1drop/two sec) added to the reaction mixture. After complete addition ofthe Grignard reagent, reaction mixture was stirred for an additional 20min at RT. An appearance of a dark-brown coloration was indicative ofgeneration of nanomaterial. After 20 min, the mixture was quenched witha single drop of degassed water, and THF was evaporated under reducedpressure at RT followed by triturating the mixture with dry pentane toprovide a green-brown-colored nanopowder (2.7 g, including materialbound to THF). The nanomaterial was dried under reduced pressure at RTfor 10 min. and could be used as such for catalytic reactions undermicellar conditions.

Solid iron nanoparticles formed from (FeCl₃+MeMgCl) were collected andanalyzed by both TEM and XPS. As illustrated in FIG. 2, TEM analysisrevealed that most of the material is composed of iron rafts, along withthe presence of significant amounts of carbon (48%), oxygen (22%),magnesium (9%) and chlorine (19%). The high levels of carbon and oxygenare associated with solvent (THF) trapped within these clusters; C—Oshows up as a shoulder in the C1s spectrum (286.5 eV; see FIG. 2 in SI).

Remarkably, only 2.4% iron in the form of iron oxides (Fe 2p3, 710.86eV) was found in this catalyst. Since each reaction calls for an initial3 mol % FeCl₃, this ultimately translates into only 720 ppm Fe presentwithin the catalyst. Analyses by AFM (FIG. 2f ) revealed an atypicalarrangement of iron atoms intermixed with other metals (i.e., mainlyMg). These particles display excellent shelf life (>1 month), andpossess virtually identical reactivity as compared to those prepared andused in situ (Scheme 4).

TGA analysis of nanomaterial revealed about 40% total weight lossbetween 60-145° C. indicating the loss of THF bound within the nanocagestructure. Material left after 145° C. was found to be very stable up to380° C. In a separate experiment, loss of catalytic activity ofnanomaterial was observed when pre-heated at 80° C. under vacuum for 12h (See SI), indicating the importance of the solvent, such as THF, toperpetuate the nanocage structure.

Upon completion of a Suzuki-Miyaura coupling, in-flask extraction with asingle organic solvent (e.g., i-PrOAc or MTBE) at ambient temperaturesleads to crude material that can be further purified in standard fashion(Scheme 3). The remaining aqueous mixture containing both nanomicellesand nanoparticles of iron can then be recycled, using the same ordifferent educts. Alternatively, with products that are solids, dilutionwith water can be followed by simple filtration to afford the targetedmaterial, ready for recrystallization and/or final purification. Thediluted filtrate can be augmented with TPGS-750-M to the original 2weight percent level and reused, thereby creating little-to-no wastewater stream. The overall E Factor associated with this chemistry, asseen previously, is only 2.95.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 on page 1 is a graphical representation showing a new approach tothe Suzuki-Miyaura coupling reaction.

FIG. 2 is a representation of a Cryo-TEM analysis of Fe/Pd nanorods inaqueous TPGS-750-M (a-c); SEM of solid nanomaterial (d-e); AFM image ofsolid nanomaterial (f). See SI for details.

FIG. 3 is a representation of a TGA analysis of Fe/Pd nanomaterial.

FIG. 4 is a representative figure showing a process for the recycling ofthe aqueous reaction mixture.

FIG. 5 shows a representative scheme of results using doped andnon-doped iron nanoparticles.

FIG. 6 shows representative results of Sonogashira Coupling Reactions.

ICP analysis was performed on the product resulting from both a couplingunder micellar conditions as well as that formed using traditionalPd-catalysis in an organic medium (Scheme 4). Aside from the higheryield, in one aspect of the method, avoidance of organic solvent, andfar lower levels of metal used, the amount of residual palladium in theproduct formed in n-butanol analyzed at 160 ppm, while that found in theproduct using Fe/ppm Pd micellar technology was only 7 ppm Pd.

The potential to apply this chemistry to an array of 1-pot sequentialreactions, heteroaryl iodide 1 containing carbamate and trimethylsilylprotecting groups was generated in situ for use in a subsequentcross-coupling reaction with alkenyl tetrafluoroborate salt 2. From thecross-coupling product 3, TMS groups were removed in situ to 4, followedby Boc removal to provide intermediate 5. Final aryl amination to 6 withbromobenzene provided an overall novel one-pot route for the synthesisof this bioactive class of 2,4,5-substituted pyrazol-3-one in 68%overall yield (Scheme 5).^([13])

The use of the catalyst system to mediate other important Pd-catalyzedreactions, such as Sonogashira couplings, was carried out employing thecoupling partners illustrated in Scheme 6. The technology mayaccommodate a broad array of functional groups and efficiency ofreaction.

Synthesis of Active Nanoparticles:

In a flame dried two-neck round-bottomed flask, anhydrous pure FeCl₃(500 mg, 3.09 mmol), XPhos (1177 mg, 2.47 mmol), and Pd(OAc)₂ (6.0 mg,0.027 mmol) were placed under an atmosphere of dry argon. The flask wasclosed with a septum, and dry THF (10 mL) was added. The reactionmixture was stirred for 20 min at RT. While maintaining a dry atmosphereat RT, MeMgCl (12.4 ml, 6.18 mmol; 0.5 M solution) in THF was veryslowly (1 drop/two sec) added to the reaction mixture. After completeaddition of the Grignard reagent, the reaction mixture was stirred foran additional 10 min at RT. An appearance of a dark-brown coloration wasindicative of generation of nanomaterial.

After 20 min, the mixture was quenched with a 0.1 mL of degassed water,and THF was evaporated under reduced pressure at RT followed bytriturating the mixture with dry pentane to provide a lightbrown-colored nanopowder (2.82 g, including material bound to THF). Thenanomaterial was dried under reduced pressure at RT for 10 min and couldbe used as such for Sonogashira reactions under micellar conditions.

General Procedure for Sonogashira Reactions:

a) Using In Situ Formation of Catalyst

Fe/ppm Pd nanoparticle formation as well as Sonogashira reactions wereair sensitive, all reactions were ran under argon. Pure FeCl₃ (97%,source Sigma-Aldrich) was doped with 320 ppm of palladium using 0.005 Msolution of Pd(OAc)₂ (source, Oakwood Chemicals) in dry CH₂Cl₂ whennanoparticles were in situ formed.

In a flame dried 4 mL microwave reaction vial, FeCl₃ (4.1 mg, 5 mol %)containing ppm levels of palladium (ca. 350 ppm), XPhos (12 mg, 5 mol %)was added under anhydrous conditions. The reaction vial was closed witha rubber septum and the mixture was evacuated-and-backfilled with argonthree times. Dry CH₂Cl₂ (1.0 mL) was added to the vial and the mixturewas stirred for 30 min at RT, after which, while maintaining the inertatmosphere, CH₂Cl₂ was evaporated under reduced pressure. MeMgCl in THF(0.2 mL, 10 mol %; 0.1 M) was added to the reaction mixture, which wasstirred at RT for one min. A freshly degassed aqueous solution of 2 wt %TPGS-750-M (1.0 mL) was added to the vial followed by sequentialaddition of aryl bromide or iodide (0.5 mmol), terminal alkyne (0.75mmol, 1.5 equiv), and triethylamine (139 μL, 1.0 mmol, 2.0 equiv). Thevial was closed with a rubber septum and evacuated-and-back-filled withargon three times. The mixture was stirred vigorously at 45° C. for thedesired time period.

After complete consumption of starting material, as monitored by TLC orGCMS, the reaction mixture was allowed to cool to RT. EtOAc or MTBE (1mL) or 5% EtOAc/MTBE was added to the reaction mixture, which wasstirred gently for 5 min. Stirring was stopped and the magnetic stir barwas removed. The organic layer was separated with the aid of acentrifuge and then dried over anhydrous sodium sulfate. The solvent wasthen evacuated under reduced pressure to obtain crude material which waspurified by flash chromatography over silica gel using EtOAc/hexanes orether/hexanes as eluent.

a) Using in Isolated Catalyst:

Under the argon atmosphere, 30 mg nanoparticles were added in to a flamedried 4 mL reaction vial. Reaction vial was closed with a rubber septumand 1.0 mL freshly degassed aqueous solution of 2 wt % TPGS-750-M wasadded to it via syringe. Reaction mixture was stirred for a minute at RTfollowed by sequential addition of aryl bromide or iodide (0.5 mmol),terminal alkyne (0.75 mmol, 1.5 equiv), and triethylamine (139 μL, 1.0mmol, 2.0 equiv). The vial was closed with a rubber septum andevacuated-and-back-filled with argon three times. The mixture wasstirred vigorously at 45° C. for the desired time period.

After complete consumption of starting material, as monitored by TLC orGCMS, the reaction mixture was allowed to cool to RT. EtOAc or MTBE (1mL) or 5% EtOAc/MTBE was added to the reaction mixture, which wasstirred gently for 5 min. Stirring was stopped and the magnetic stir barwas removed. The organic layer was separated with the aid of acentrifuge and then dried over anhydrous sodium sulfate. The solvent wasthen evacuated under reduced pressure to obtain crude material which waspurified by flash chromatography over silica gel using EtOAc/hexanes orether/hexanes as eluent.

Synthesis of Active Nanoparticles:

In a flame dried two-neck round-bottomed flask, anhydrous pure FeCl₃(500 mg, 3.09 mmol), XPhos (1180 mg, 2.47 mmol), and Pd(OAc)₂ (6.0 mg,0.027 mmol) were placed under an atmosphere of dry argon. The flask wasclosed with a septum, and dry THF (10 mL) was added. The reactionmixture was stirred for 20 min at RT. While maintaining a dry atmosphereat RT, MeMgCl (12.4 ml, 6.18 mmol; 0.5 M solution) in THF was veryslowly (1 drop/two sec) added to the reaction mixture. After completeaddition of the Grignard reagent, the reaction mixture was stirred foran additional 10 min at RT. An appearance of a dark-brown coloration wasindicative of generation of nanomaterial.

After 20 min, the mixture was quenched with a 0.1 mL of degassed water,and THF was evaporated under reduced pressure at RT followed bytriturating the mixture with dry pentane to provide a lightbrown-colored nanopowder (2.82 g, including material bound to THF). Thenanomaterial was dried under reduced pressure at RT for 10 min and couldbe used as such for Sonogashira reactions under micellar conditions.

General Procedure for Sonogashira Reactions:

a) Using In Situ Formation of Catalyst:

Fe/ppm Pd nanoparticle formation as well as Sonogashira reactions wereair sensitive; all reactions were ran under argon. Pure FeCl₃ (97%,source Sigma-Aldrich) was doped with 320 ppm of palladium using 0.005 Msolution of Pd(OAc)₂ (Oakwood Chemicals) in dry CH₂Cl₂ whennanoparticles were in situ formed.

In a flame dried 4 mL microwave reaction vial, FeCl₃ (4.1 mg, 5 mol %)containing ppm levels of palladium (ca. 350 ppm), XPhos (12 mg, 5 mol %)was added under anhydrous conditions. The reaction vial was closed witha rubber septum and the mixture was evacuated-and-backfilled with argonthree times. Dry CH₂Cl₂ (1.0 mL) was added to the vial and the mixturewas stirred for 30 min at RT, after which, while maintaining the inertatmosphere, CH₂Cl₂ was evaporated under reduced pressure. MeMgCl in THF(0.2 mL, 10 mol %; 0.1 M) was added to the reaction mixture, and stirredat RT for one min. A freshly degassed aqueous solution of 2 wt %TPGS-750-M (1.0 mL) was added to the vial followed by sequentialaddition of N-(2-iodophenyl)acetamide (138 mg, 0.5 mmol),1-ethynyl-3,5-bis(trifluoromethyl)benzene (179 mg, 0.75 mmol, 1.5 equiv)and triethylamine (139 μL, 1.0 mmol, 2.0 equiv). The vial was closedwith a rubber septum and evacuated-and-back-filled with argon 3 times.The mixture was stirred vigorously at 45° C. for the 32 h.

After complete consumption of starting material by TLC or GCMS, thereaction mixture was allowed to cool to RT. 2 mL EtOAc was added to thereaction mixture, which was stirred gently for 5 min. Stirring wasstopped and the magnetic stir bar was removed. The organic layer wasseparated with the aid of a centrifuge. Similar extraction procedure wasrepeated and combined organic layer was dried over anhydrous sodiumsulfate. The solvent was then evacuated under reduced pressure to obtaincrude material which was purified by flash chromatography over silicagel using EtOAc/hexanes (1:49) as eluent. R_(f) 0.35 in EtOAc/hexanes,white solid, yield 91% (175 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d,J=8.8 Hz, 1H), 7.97 (s, 2H), 7.86 (s, 1H), 7.50 (dd, J=8.4 and 1.2 Hz,1H), 7.43-7.39 (m, 1H), 7.32 (br. s, 1H), 7.06 (t, J=8.0 Hz, 1H), 3.83(s, 3H); ¹⁹F NMP (376 MHz, CDCl₃) δ −63.2; ¹³C NMR (101 MHz, CDCl₃) δ−153.7, 139.4, 132.4, 132.3 (q, J_((C,F))=34 Hz), 131.6, 131.5, 131.0,125.0, 123.0, 123 (q, J_((C,F))=274 Hz), 122.2 (septet, J_((C,F))=3.8Hz), 118.3, 110.3, 93.0, 87.9, and 52.7. ppm.

a) Using in Isolated Catalyst:

Under the argon atmosphere, 30 mg nanoparticles were added in to a flamedried 4 mL reaction vial. Reaction vial was closed with a rubber septumand 1.0 mL freshly degassed aqueous solution of 2 wt % TPGS-750-M wasadded via syringe. Reaction mixture was stirred for a minute at RTfollowed by sequential addition of N-(2-iodophenyl)acetamide (131 mg,0.5 mmol), 1-ethynyl-3,5-bis(trifluoromethyl)benzene (179 mg, 0.75 mmol,1.5 equiv), and triethylamine (139 μL, 1.0 mmol, 2.0 equiv). The vialwas closed with a rubber septum and evacuated-and-back-filled with argonthree times. The mixture was stirred vigorously at 45° C. for 32 hours.

After complete consumption of starting material by TLC or GCMS, thereaction mixture was allowed to cool to RT. 2 mL EtOAc was added to themixture and stirred for 5 min. Stirring was stopped and the magneticstir bar was removed. The organic layer was separated with the aid of acentrifuge. Similar extraction procedure was repeated and combinedorganic layer was dried over anhydrous sodium sulfate. The solvent wasthen evacuated under reduced pressure to obtain crude material which waspurified by flash chromatography over silica gel using EtOAc/hexanes(1:49) as eluent. R_(f)0.35 in EtOAc/hexanes, white solid, yield 91%(175 mg). ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=8.8 Hz, 1H), 7.97 (s,2H), 7.86 (s, 1H), 7.50 (dd, J=8.4 and 1.2 Hz, 1H), 7.43-7.39 (m, 1H),7.32 (br. s, 1H), 7.06 (t, J=8.0 Hz, 1H), 3.83 (s, 3H); ¹⁹F NMP (376MHz, CDCl₃) δ −63.2; ¹³C NMR (101 MHz, CDCl₃) δ −153.7, 139.4, 132.4,132.3 (q, J_((C,F))=34 Hz), 131.6, 131.5, 131.0, 125.0, 123.0, 123 (q,J_((C,F))=274 Hz), 122.2 (septet, J_((C,F))=3.8 Hz), 118.3, 110.3, 93.0,87.9 and 52.7. ppm.

As disclosed herein, a new catalyst system may be employed for valuablecross-couplings or cross-coupling reactions that utilizes ironnanoparticles doped naturally, or externally, with ppm levels of Pd.Coupling reactions, such as the Suzuki-Miyaura reactions studied areenabled by micellar catalysis that provides the nano reactors that houseand deliver the reaction partners to the catalyst. The conditions arevery mild, while efficiencies are high. Both the catalyst and aqueousmedium in which the reactions occur are not only recyclable, but alsoenvironmentally responsible based on the very low E Factors associatedwith this chemistry.

The foregoing examples of the related art and limitations are intendedto be illustrative and not exclusive. Other limitations of the relatedart will become apparent to those of skill in the art upon a reading ofthe specification and a study of the drawings or figures as providedherein. In addition to the exemplary embodiments, aspects and variationsdescribed above, further embodiments, aspects and variations will becomeapparent by reference to the drawings and figures and by examination ofthe following descriptions.

Definitions

Unless specifically noted otherwise herein, the definitions of the termsused are standard definitions used in the art of organic synthesis andpharmaceutical sciences. Exemplary embodiments, aspects and variationsare illustratived in the figures and drawings, and it is intended thatthe embodiments, aspects and variations, and the figures and drawingsdisclosed herein are to be considered illustrative and not limiting.

An “alkyl” group is a straight, branched, saturated or unsaturated,aliphatic group having a chain of carbon atoms, optionally with oxygen,nitrogen or sulfur atoms inserted between the carbon atoms in the chainor as indicated. A C₁-C₂₀alkyl or C₁₋₂₀alkyl, for example, includesalkyl groups that have a chain of between 1 and 20 carbon atoms, andinclude, for example, the groups methyl, ethyl, propyl, isopropyl,vinyl, allyl, 1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl,1,3-butadienyl, penta-1,3-dienyl, penta-1,4-dienyl, hexa-1,3-dienyl,hexa-1,3,5-trienyl, and the like. An alkyl group may also berepresented, for example, as a —(CR¹R²)_(m)— group where R¹ and R² areindependently hydrogen or are independently absent, and for example, mis 1 to 8, and such representation is also intended to cover bothsaturated and unsaturated alkyl groups.

An alkyl as noted with another group such as an aryl group, representedas “arylalkyl” for example, is intended to be a straight, branched,saturated or unsaturated aliphatic divalent group with the number ofatoms indicated in the alkyl group (as in C₁-C₂₀alkyl, for example)and/or aryl group (as in C₅-C₁₄aryl, for example) or when no atoms areindicated means a bond between the aryl and the alkyl group.Nonexclusive examples of such group include benzyl, phenethyl and thelike.

An “alkylene” group is a straight, branched, saturated or unsaturatedaliphatic divalent group with the number of atoms indicated in the alkylgroup; for example, a —C₁-C₃ alkylene- or —C₁-C₃alkylenyl-.

The term “alkynyl” refers to a hydrocarbon group of 2 to 24 carbon atomswith a structural formula containing at least one carbon-carbon triplebond. The alkynyl group can be unsubstituted or substituted with one ormore groups including, but not limited to, alkyl, cycloalkyl, alkoxy,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, anthracene, and the like. The aryl group can besubstituted or unsubstituted. The aryl group can be substituted with oneor more groups as disclosed herein, including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, —NH₂, carboxylic acid, ester, ether, halide,hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as describedherein. The term “biaryl” is a specific type of aryl group and isincluded in the definition of “aryl.” In addition, the aryl group can bea single ring structure or comprise multiple ring structures that areeither fused ring structures or attached via one or more bridging groupssuch as a carbon-carbon bond. For example, biaryl can be two aryl groupsthat are bound together via a fused ring structure, as in naphthalene,or are attached via one or more carbon-carbon bonds, as in biphenyl.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl and the like. The term “heterocycloalkyl” is atype of cycloalkyl group and is included within the meaning of the term“cycloalkyl,” where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur or phosphorus. The cycloalkyl group and heterocycloalkylgroup can be substituted or unsubstituted. The cycloalkyl group andheterocycloalkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether,halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

A “cyclyl” such as a monocyclyl or polycyclyl group includes monocyclic,or linearly fused, angularly fused or bridged polycycloalkyl, orcombinations thereof. Such cyclyl group is intended to include theheterocyclyl analogs. A cyclyl group may be saturated, partiallysaturated or aromatic.

“Halogen” or “halo” means fluorine, chlorine, bromine or iodine.

The terms “heterocycle” or “heterocyclyl,” as used herein can be usedinterchangeably and refer to single and multi-cyclic aromatic ornon-aromatic ring systems in which at least one of the ring members isother than carbon. The term is inclusive of, but not limited to,“heterocycloalkyl”, “heteroaryl”, “bicyclic heterocycle” and “polycyclicheterocycle.” Heterocycle includes pyridine, pyrimidine, furan,thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole,imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole,1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including,1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazoleand 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including1,2,4-triazine and 1,3,5-triazine, tetrazine, including1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine,azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. Aheterocyclyl group can also be a C₂ heterocyclyl, C₂-C₃ heterocyclyl,C₂-C₄ heterocyclyl, C₂-C₅ heterocyclyl, C₂-C₆ heterocyclyl, C₂-C₇heterocyclyl, C₂-C₈ heterocyclyl, C₂-C₉ heterocyclyl, C₂-C₁₀heterocyclyl, C₂-C₁₁ heterocyclyl, and the like up to and including aC₂-C₁₈ heterocyclyl. For example, a C₂ heterocyclyl comprises a groupwhich has two carbon atoms and at least one heteroatom, including, butnot limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl andthe like. Alternatively, for example, a C5 heterocyclyl comprises agroup which has five carbon atoms and at least one heteroatom,including, but not limited to, piperidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like.

A “heteroaryl,” refers to an aromatic group that has at least oneheteroatom incorporated within the ring of the aromatic group. Examplesof heteroatoms include, but are not limited to, nitrogen, oxygen, sulfurand phosphorus. The heteroaryl group can be substituted orunsubstituted. The heteroaryl group can be substituted with one or moregroups including, alkyl, cycloalkyl, alkoxy, amino, ether, halide,hydroxy, nitro, silyl or thiol. Heteroaryl groups can be monocyclic, orfused ring systems. Heteroaryl groups include, but are not limited to,furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl,pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl,benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl,pyrazolopyridinyl, and pyrazolopyrimidinyl. Other examples of heteroarylgroups include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl,quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl,benzo[c][1,2,5]oxadiazolyl and pyrido[2,3-b]pyrazinyl.

The term “pseudohalides”, by themselves or as part of anothersubstituent, refers to species resembling halides in their charge andreactivity, and are generally a good leaving group in a reaction, suchas a substitution reaction. Examples are azides (NNN—), isocyanate(—NCO), isocyanide, (CN—), triflate (—OSO₂SF₃) and mesylate (CH₃SO₂O—).

“Substituted or unsubstituted” or “optionally substituted” means that agroup such as, for example, alkyl, aryl, heterocyclyl, C₁-C₈cycloalkyl,heterocyclyl(C₁-C₈)alkyl, aryl(C₁-C₈)alkyl, heteroaryl,heteroaryl(C₁-C₈)alkyl, and the like, unless specifically notedotherwise, may be unsubstituted or, may substituted by 1, 2 or 3substituents selected from the group such as halo, nitro,trifluoromethyl, trifluoromethoxy, methoxy, carboxy, —NH₂, —OH, —OMe,—SH, —NHCH₃, —N(CH₃)₂, —SMe, cyano and the like.

REFERENCES

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The entire disclosures of all documents cited throughout thisapplication are incorporated herein by reference. While a number ofexemplary embodiments, aspects and variations have been provided herein,those of skill in the art will recognize certain modifications,permutations, additions and combinations and certain sub-combinations ofthe embodiments, aspects and variations. It is intended that thefollowing claims are interpreted to include all such modifications,permutations, additions and combinations and certain sub-combinations ofthe embodiments, aspects and variations are within their scope.

What is claimed is:
 1. An aqueous micellar composition in a reactionsolvent for enabling cross-coupling reactions containing organometallicnanoparticles (NPs) as catalyst, comprising: a) an element selected fromthe group consisting of Fe, C, H, O, Mg, and a halide, or the entirecombination thereof; and b) palladium (Pd), or at least one other metalselected from the group consisting of Pt, Au, Ni, Co, Cu and Mn, or amixture thereof; wherein the catalyst (NPs) is prepared from a reductionof an iron salt or an iron complex in a solvent and in the presence of aligand using a reducing agent.
 2. The aqueous micellar composition ofclaim 1, wherein the iron is selected from the group consisting of aFe(II) or Fe(III) salt, a Fe(II) salt precursor or Fe(III) saltprecursor.
 3. The aqueous micellar composition of claim 1, wherein thePd is naturally present in the iron salt or the iron complex in amountsless than or equal to 1 ppm, 10 ppm, 50 ppm, 100 ppm, 200 ppm, 300 ppm,400 ppm or 500 ppm relative to the iron salt or iron complex.
 4. Theaqueous micellar composition of claim 3, where the amount of Pd presentis controlled by external addition of a palladium salt to an iron salt.5. The aqueous micellar composition of claim 3, wherein the reducingreagent is a Grignard reagent selected from the group consisting ofMeMgCl, MeMgBr, MeMgI, EtMgCl, EtMgBr, EtMgI, i-PrMgCl, i-PrMgBr,i-PrMgI, PhMgCl, PhMgBr, PhMgI, n-hexyl-MgBr, n-hexyl-MgCl,n-hexyl-MgBr, n-hexyl-MgCl, n-hexyl-MgI, NaBH₄, liBH₄, BH₃-THF,BH₃—SMe₂, borane, DIBAL-H and LiAlH₄; and mixtures thereof.
 6. Theaqueous micellar composition of claim 1 further comprising a surfactant,wherein the surfactant is selected from the group consisting ofTPGS-500, TPGS-500-M, TPGS-750, TPGS-750-M, TPGS-1000 and TPGS-1000-M,Nok and PTS, or a mixture thereof.
 7. The aqueous micellar compositionof claim 1, further comprising a ligand selected from the groupconsisting of PPh₃, (o-Tol)₃P, (p-Tol)₃P, dppf, dtbpf, BiDime, Tangphos,IMes, IPr, SPhos, t-BuSPhos, XPhos, t-BuXPhos, BrettPhos andt-BuBrettPhos, and HandaPhos or an analog thereof.
 8. The aqueousmicellar composition of claim 1, wherein the iron metal complex asnanoparticles is heterogeneous and can be isolated from the composition,stored and recycled.
 9. The composition of claim 1, wherein the reactionsolvent is water, and the reaction solvent further comprising an organicsolvent, wherein the organic co-solvent is present in at least 5%, 10%,20%, 30%, 40%, 50%, 70%, 80% or at least 90% wt/wt.